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TSC2

Introduction

Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene.

Function

Function

Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. Hamartin coded by the gene TSC1 functions as a facilitator of Hsp90 in chaperoning of Tuberin, therefore preventing its ubiquitination and degradation in the proteasome.[1] Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.[2] Mutations in TSC2 can cause Lymphangioleiomyomatosis, a disease caused by the enlargement of tissue in the lungs, creating cysts and tumours and causing difficulty breathing. Because Tuberin regulates cell size, along with the protein Hamartin, mutations to TSC1 and TSC2 genes may prevent the control of cell growth in the lungs of individuals.[1]

Signaling Pathways

Signaling Pathways

Pharmacological inhibition of ERK1/2 restores GSK3Ξ² activity and protein synthesis levels in a model of tuberous sclerosis.[3]

Interactions

Interactions

TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,[4][5] and TBC1D7.

TSC2 has been reported to interact with several other proteins that are not a part of the TSC complex including:

See also

See also

References

References

  1. ↑ 1.0 1.1 1.2 1.3 Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M (December 2017). “Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients”. The EMBO Journal. 36 (24): 3650–3665. doi:10.15252/embj.201796700. PMCΒ 5730846. PMIDΒ 29127155.
  2. ↑ “Entrez Gene: TSC2 tuberous sclerosis 2”.
  3. ↑ Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M (June 2017). “Inhibition of ERK1/2 Restores GSK3Ξ² Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis”. Scientific Reports. 7 (1): 4174. doi:10.1038/s41598-017-04528-5. PMCΒ 5482840. PMIDΒ 28646232.
  4. ↑ Orlova KA, Crino PB (January 2010). “The tuberous sclerosis complex”. Annals of the New York Academy of Sciences. 1184: 87–105. doi:10.1111/j.1749-6632.2009.05117.x. PMCΒ 2892799. PMIDΒ 20146692.
  5. ↑ Li Y, Inoki K, Guan KL (September 2004). “Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity”. Molecular and Cellular Biology. 24 (18): 7965–75. doi:10.1128/MCB.24.18.7965-7975.2004. PMCΒ 515062. PMIDΒ 15340059.
  6. ↑ Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (September 2002). “Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin”. The Journal of Biological Chemistry. 277 (38): 35364–70. doi:10.1074/jbc.M205838200. PMIDΒ 12167664.
  7. ↑ 7.0 7.1 Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (September 2004). “Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase”. Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13489–94. doi:10.1073/pnas.0405659101. PMCΒ 518784. PMIDΒ 15342917.
  8. ↑ 8.0 8.1 Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). “The tuberin-hamartin complex negatively regulates beta-catenin signaling activity”. The Journal of Biological Chemistry. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMIDΒ 12511557.
  9. ↑ 9.0 9.1 Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J (December 2006). “Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway”. The Journal of Biological Chemistry. 281 (52): 40242–51. doi:10.1074/jbc.M608116200. PMIDΒ 17077083.
  10. ↑ Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (September 2006). “TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth”. Cell. 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. PMIDΒ 16959574.
  11. ↑ Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (April 2005). “Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis”. Cell. 121 (2): 179–93. doi:10.1016/j.cell.2005.02.031. PMIDΒ 15851026.
  12. ↑ Gan B, Yoo Y, Guan JL (December 2006). “Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth”. The Journal of Biological Chemistry. 281 (49): 37321–9. doi:10.1074/jbc.M605241200. PMIDΒ 17043358.
  13. ↑ Murthy V, Han S, Beauchamp RL, Smith N, Haddad LA, Ito N, Ramesh V (January 2004). “Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex”. The Journal of Biological Chemistry. 279 (2): 1351–8. doi:10.1074/jbc.M310208200. PMIDΒ 14559897.
  14. ↑ Inoki K, Zhu T, Guan KL (November 2003). “TSC2 mediates cellular energy response to control cell growth and survival”. Cell. 115 (5): 577–90. doi:10.1016/S0092-8674(03)00929-2. PMIDΒ 14651849.
  15. ↑ Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (July 2004). “The LKB1 tumor suppressor negatively regulates mTOR signaling”. Cancer Cell. 6 (1): 91–9. doi:10.1016/j.ccr.2004.06.007. PMIDΒ 15261145.
  16. ↑ 16.0 16.1 Castro AF, Rebhun JF, Clark GJ, Quilliam LA (August 2003). “Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner”. The Journal of Biological Chemistry. 278 (35): 32493–6. doi:10.1074/jbc.C300226200. PMIDΒ 12842888.
  17. ↑ Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RS (August 2002). “Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin”. Archives of Biochemistry and Biophysics. 404 (2): 210–7. doi:10.1016/S0003-9861(02)00300-4. PMIDΒ 12147258.
  18. ↑ Inoki K, Li Y, Xu T, Guan KL (August 2003). “Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling”. Genes & Development. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMCΒ 196227. PMIDΒ 12869586.
  19. ↑ Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (June 2003). “Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2”. Molecular Cell. 11 (6): 1457–66. doi:10.1016/S1097-2765(03)00220-X. PMIDΒ 12820960.
  20. ↑ Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (June 2003). “Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins”. Nature Cell Biology. 5 (6): 578–81. doi:10.1038/ncb999. PMIDΒ 12771962.
  21. ↑ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (April 2005). “Rheb binds and regulates the mTOR kinase”. Current Biology. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMIDΒ 15854902.
  22. ↑ Rolfe M, McLeod LE, Pratt PF, Proud CG (June 2005). “Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2)”. The Biochemical Journal. 388 (Pt 3): 973–84. doi:10.1042/BJ20041888. PMCΒ 1183479. PMIDΒ 15757502.
  23. ↑ Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (August 2004). “Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin”. The Journal of Biological Chemistry. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMIDΒ 15175323.
  24. ↑ Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y (March 2008). “E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6”. Genes to Cells. 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMIDΒ 18298802.
  25. ↑ Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ (October 2002). “Identification and characterization of the interaction between tuberin and 14-3-3zeta”. The Journal of Biological Chemistry. 277 (42): 39417–24. doi:10.1074/jbc.M204802200. PMIDΒ 12176984.
Further reading

Further reading

External links